Treatment of attention-deficit/hyperactivity disorder

ABSTRACT

A group of propanamines, norepinephrine uptake inhibitors, are used to treat attention-deficit/hyperactivity disorder.

This application claims the benefit of U.S. Provisional Application No.60/001,373, filed Jul. 24, 1995, and U.S. Provisional Application No.60/006,349, filed Nov. 8, 1995.

This application claims the benefit of U.S. Provisional Application No.60/001,373, filed Jul. 24, 1995, and U.S. Provisional Application No.60/006,349, filed Nov. 8, 1995.

FIELD OF THE INVENTION

The invention belongs to the fields of pharmaceutical chemistry andpsychiatric medicine, and provides a method of treatment of thepsychiatric disorder known as attention-deficit/hyperactivity disorder.

BACKGROUND OF THE INVENTION

For some decades it has been recognized that a significant number ofchildren are persistently hyperactive and have an attention span soshort as to be disabling in school and in many personal relationships.Such children in earlier times would no doubt have been dismissed asincorrigible and punished or even confined in an institution. Some longtime ago, however, it was realized that these children cannot controltheir hyperactivity and inattention, and the medical professions beganto try to help them. Methylphenidate (Ritalin™) has been used for sometime to treat such children and it often significantly improves theirability to function and coexist with other people at school and at home.However, the drug has the disadvantages of requiring several doses perday, and producing a rebound effect as the effect of each dose fadesaway. Further, the drug causes sleeplessness and lack of appetite insome patients. Methylphenidate has both noradrenergic and dopaminergicactivities.

Imipramine, desipramine, nortriptyline, amitriptyline and clomipramineare also used in some cases of attention-deficit/hyperactivity disorder(ADHD). Those tricyclic drugs, however, have a number of physiologicalmechanisms and, as a class, tend to produce a number of side effects andrequire careful supervision and dose titration.

In the last decade, psychiatrists have realized that ADHD is not only adisorder of childhood, but often continues in the adult. It is obviousthat hyperactivity and short attention span cause grave disruption in anadult's life, but it is only recently that such patients have been ableto obtain any treatment.

The need for a safe and convenient treatment for ADHD, applicable toboth children and adults and without the disadvantages possessed bymethylphenidate continues to be a concern of the psychiatric profession.

SUMMARY OF THE INVENTION

The present invention provides a method of treatingattention-deficit/hyperactivity disorder comprising the administrationto a patient in need of such treatment of an effective amount ofduloxetine, or of a compound of the formula ##STR1## wherein X=C₁ -C₄alkylthio, and Y=C₁ -C₂ alkyl or a stereoisomer thereof, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, isusually administered as the hydrochloride salt and as the (+)enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which showsits high potency. The word "duloxetine" will be used here to refer toany acid addition salt or the free base of the molecule.

The compounds of formula I were described in U.S. Pat. No. 5,281,624, ofGehlert, Robertson and Wong, and in Gehlert, et al., Life Sciences,56(22), 1915-1920, 1995. The compounds are there taught to be inhibitorsof norepinephrine reuptake in the brain. It is also explained that thecompounds exist as stereoisomers, and that they accordingly include notonly the racemates, but also the isolated individual isomers. Forexample, the compounds of formula I include the following exemplaryspecies.

N-ethyl-3-phenyl-3-(2-methylthiophenoxy) propylamine benzoate

(R)-N-methyl-3-phenyl-3-(2-propylthiophenoxy) propylamine hydrochloride

(S)-N-ethyl-3-phenyl-3-(2-butylthiophenoxy) propylamine

N-methyl-3-phenyl-3-(2-ethylthiophenoxy) propylamine malonate

(S)-N-methyl-3-phenyl-3-(2-t-butylthiophenoxy) propylaminenaphthalene-2-sulfonate

(R)-N-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine

(S)-N-methyl-3-phenyl-3-(2-t-butylthiophenoxy) propylaminenaphthalene-2-sulfonate

The compounds used in this invention are safe drugs, and their use inADHD, in both adults and children, is a superior treatment for thatdisorder because of their improved safety. The compounds areparticularly selective, having few if any physiological effects besidesthat on norepinephrine processing, and therefore are free of sideeffects and unwanted activities. Further, they are effective atrelatively low doses, as discussed below, and may safely and effectivelybe administered once per day. Thus, difficulties created by the multipledosing of patients, who are children and disorganized adults, arecompletely avoided.

The present invention is described as a method of treating ADHD. It isnot intended, of course, that every use of the invention will result ina complete cure of the disorder. Treatment of psychiatric disorders isnot that precise. It is intended, however, that the use of the inventionwill result in improvement of the treated ADHD patient which willapproach complete cure in some cases. In other cases, a lesser degree ofimprovement, still benefiting the patient, will be obtained. Suchtreatment is carried out by administering an effective amount of thechosen compound. It will be understood that amount is an amount whichproduces treatment of the patient at hand.

The effective dose of a compound of this invention for ADHD is in therange from about 1 mg/day to about 100 mg/day. The preferred adult doseis in the range from about 5 to about 80 mg/day, and a more highlypreferred adult dose is from about 10 to about 60 mg/day. The children'sdose of course is smaller, in the range from about 1 to about 70 mg/day,more preferably from about 5 to about 60 mg/day and still morepreferably from about 5 to about 50 mg/day. The optimum dose for eachpatient, as always, must be set by the physician in charge of the case,taking into account the patient's size, other medications which thepatient requires, severity of the disorder and all of the othercircumstances of the patient.

Since the compounds are readily orally absorbed and require onlyonce/day administration, there is little or no reason to administer themin any other way than orally. They may be produced in the form of aclean, stable crystal, and thus are easily formulated in the usual oralpharmaceutical forms, such as tablets, capsules, suspensions, and thelike. The usual methods of pharmaceutical scientists are applicable.They may usefully be administered, if there is any reason to do so in aparticular circumstance, in other pharmaceutical forms, such asinjectable solutions, depot injections, suppositories and the like,which are well known to and understood by pharmaceutical scientists. Itwill substantially always be preferred, however, to administer acompound as a tablet or capsule and such pharmaceutical forms arerecommended.

A preferred duloxetine enteric formulation is a pellet formulationcomprising a) a core consisting of duloxetine and a pharmaceuticallyacceptable excipient; b) an optional separating layer; c) an entericlayer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS)and a pharmaceutically acceptable excipient; d) an optional finishinglayer. The following example demonstrates the preparation of a preferredsuch formulation.

Example

    ______________________________________                                        10 mg Duloxetine base/capsule                                                 Bill of Materials                                                             ______________________________________                                        Beads                                                                         Sucrose - starch nonpareils,                                                  20-25 mesh               60.28   mg                                           Duloxetine layer                                                              Duloxetine               11.21                                                Hydroxypropylmethylcellulose                                                                           3.74                                                 Separating layer                                                              Hydroxypropylmethylcellulose                                                                           2.51                                                 Sucrose                  5.00                                                 Talc, 500 mesh           10.03                                                Enteric layer                                                                 HPMCAS, LF grade, Shin-Etsu Chemical                                                                   25.05                                                Co., Tokyo, Japan                                                             Triethyl citrate         5.00                                                 Talc, 500 mesh           7.52                                                 Finishing layer                                                               Hydroxypropylmethylcellulose                                                                           8.44                                                 Titanium dioxide         2.81                                                 Talc                     Trace                                                                         141.60  mg                                           ______________________________________                                    

The duloxetine layer was built up by suspending duloxetine in a 4% w/wsolution of the hydroxypropylmethylcellulose in water, and milling thesuspension with a CoBall Mill (Fryma Mashinen AG, Rheinfelden,Switzerland) model MS-12. A fluid bed dryer with a Wurster column wasused to make this product, at a batch size of 1.0 kg. The separatinglayer was added from a 4% w/w solution of thehydroxypropylmethylcellulose in water, in which the sucrose was alsodissolved.

In order to prepare the enteric coating suspension, purified water wascooled to 10° C. and the polysorbate, triethyl citrate and siliconeemulsion were added and dispersed or dissolved. Then the HPMCAS and talcwere added and agitated until homogeneity was obtained, and the HPMCASwas fully neutralized by addition of ammonium hydroxide until solutionof the polymer was complete. To this suspension, acarboxymethylcellulose aqueous solution, 0.5% w/w, was added and blendedthoroughly. The enteric suspension was maintained at 20° C. during thecoating process. The enteric suspension was then added to the partiallycompleted pellets in the Wurster column at a spray rate of about 15ml/min, holding the temperature of the inlet air at about 50° C. Theproduct was dried in the Wurster at 50° C. when the enteric suspensionhad been fully added, and then dried on trays for 3 hours in a dry houseat 60° C. A finishing layer was then applied which consisted of a 4.5%w/w/ hydroxypropylmethylcellulose solution containing titanium dioxideand propylene glycol as plasticizer. The pellets were completely driedin the fluid bed dryer and then were then filled in size 3 gelatincapsules.

The ADHD patient is rather readily recognized, and most people have beenin contact with children, if not adults, who exhibit some or all of thesymptoms of the disorder. The best description of the disorder is thediagnostic criteria for ADHD, published by the American PsychiatricAssociation in the Diagnostic and Statistical Manual of MentalDisorders, Fourth Version (1994), as follows.

Diagnostic criteria for Attention-Deficit/Hyperactivity Disorder

A. Either (1) or (2):

(1) six (or more) of the following symptoms of inattention havepersisted for at least 6 months to a degree that is maladaptive andinconsistent with developmental level:

Inattention

(a) often fails to give close attention to details or makes carelessmistakes in schoolwork, work, or other activities

(b) often has difficulty sustaining attention in tasks or playactivities

(c) often does not seem to listen when spoken to directly

(d) often does not follow through on instructions and fails to finishschoolwork, chores, or duties in the workplace (not due to oppositionalbehavior or failure to understand instructions)

(e) often has difficulty organizing tasks and activities

(f) often avoids, dislikes, or is reluctant to engage in tasks thatrequire sustained mental effort (such as schoolwork or homework)

(g) often loses things necessary for tasks or activities (e.g., toys,school assignments, pencils, books, or tools)

(h) is often easily distracted by extraneous stimuli

(i) is often forgetful in daily activities

(2) six (or more) of the following symptoms of hyperactivity-impulsivityhave persisted for at least 6 months to a degree that is maladaptive andinconsistent with developmental level:

Hyperactivity

(a) often fidgets with hands or feet or squirms in seat

(b) often leaves seat in classroom or in other situations in whichremaining seated is expected

(c) often runs about or climbs excessively in situations in which it isinappropriate (in adolescents or adults, may be limited to subjectivefeelings of restlessness)

(d) often has difficulty playing or engaging in leisure activitiesquietly

(e) is often "on the go" or often acts as if "driven by a motor"

(f) often talks excessively

Impulsivity

(g) often blurts out answers before questions have been completed

(h) often has difficulty awaiting turn

(i) often interrupts or intrudes on others (e.g., butts intoconversations or games)

B. Some hyperactive-impulsive or inattentive symptoms that causedimpairment were present before age 7 years.

C. Some impairment from the symptoms is present in two or more settings(e.g., at school or work! and at home).

D. There must be clear evidence of clinically significant impairment insocial, academic, or occupational functioning.

E. The symptoms do not occur exclusively during the course of aPervasive Developmental Disorder, Schizophrenia, or other PsychoticDisorder and are not better accounted for by another mental disorder(e.g., Mood Disorder, Anxiety Disorder, Dissociative Disorder, or aPersonality Disorder).

It will be seen that ADHD is a disorder made up of two components, theattention deficit component and the hyperactivity component, which areto a degree independent. Treatment with the compounds is effective inpatients who are primarily suffering from either component or from thecombined disorder.

While ADHD is still primarily regarded as a disorder of children, it isnow understood that many ADHD patients, as many as 50%, continue tosuffer from the disorder as they grow through adolescence intoadulthood. Biederman and associates have extensively studied the adultADHD patient, and have found numerous cases. See, for example,Biederman, et al., Am. J. Psychiatry 150, 1792-98 (1993). They foundthat cases of adult ADHD were frequently found among the parents andadult siblings of childhood ADHD patients. Thus, it appears that thedisease is not only carried forward into adulthood, but is inheritable.

The Biederman, et al. article cited immediately above, as well asanother article by the same authors, Am. J. Psychiatry 148, 564-77(1991), reports studies of ADHD patients who also have one or more otherpsychiatric disorders. The authors indicate that such psychiatricco-morbidity is quite common among ADHD patients and, naturally, cloudthe diagnosis and treatment of such patients. The compounds areeffective in the treatment of ADHD, even though the situation of thetreated patient may be complicated by co-morbidity with one or moreadditional disorders.

The mere listing of the above diagnostic criteria indicates theseriousness of ADHD and the damage which it does to the patient. Aperson having a moderately severe case of ADHD is substantially entirelyunable to concentrate and hence unable to do meaningful work or study;is a continuing distraction and nuisance to those around her or him,because of the uselessly impulsive activity which the disorder causes;and consumes his or her family in cleaning up and repairing the damageand disruption which he or she causes. Such a patient of school age maysubstantially damage the teacher's ability to accomplish the class'goals, because the ADHD child will continually disrupt the class,distract the other children and consume the teacher's effort. Thus, itis readily apparent that an improved treatment of ADHD is needed, andthat the present invention is accordingly important to many people.

The method of the present invention is effective in the treatment ofpatients who are children, adolescents or adults, and there is nosignificant difference in the symptoms or the details of the manner oftreatment among patients of different ages. In general terms, however,for purposes of the present invention, a child is considered to be apatient below the age of puberty, an adolescent is considered to be apatient from the age of puberty up to about 18 years of age, and anadult is considered to be a patient of 18 years or older.

We claim:
 1. A method of treating attention-deficit/hyperactivitydisorder comprising administering to a patient in need of such treatmentan effective amount of a compound of the formula ##STR2## wherein X=C₁-C₄ alkylthio, and Y=C₁ -C₂ alkyl or a stereoisomer thereof, or apharmaceutically acceptable salt thereof.
 2. A method of claim 1 whereinthe compound is N-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine ora stereoisomer thereof, or a pharmaceutically acceptable salt thereof.3. A method of claim 1 wherein the predominantly inattentive type ofattention-deficit/hyperactivity disorder is treated.
 4. A method ofclaim 1 wherein the predominantly hyperactive-impulsive type ofattention-deficit/hyperactivity disorder is treated.
 5. A method ofclaim 1 wherein the combined type of attention-deficit/hyperactivitydisorder is treated.
 6. A method of claim 1 wherein the patient is achild.
 7. A method of claim 1 wherein the patient is an adolescent.
 8. Amethod of claim 1 wherein the patient is an adult.
 9. A method of claim3 wherein the compound isN-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine or a stereoisomerthereof, or a pharmaceutically acceptable salt thereof.
 10. A method ofclaim 4 wherein the compound isN-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine or a stereoisomerthereof, or a pharmaceutically acceptable salt thereof.
 11. A method ofclaim 5 wherein the compound isN-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine or a stereoisomerthereof, or a pharmaceutically acceptable salt thereof.
 12. A method ofclaim 9 wherein the patient is a child.
 13. A method of claim 10 whereinthe patient is a child.
 14. A method of claim 11 wherein the patient isa child.